Table of Neurotransmitters

Synaptic Transmission
Neuromuscular Transmission
Neurotransmitter Receptors
Acetylcholine
Cholinergic Agonists and Antagonists
Catecholamines
Serotonin, 5HT
GABA
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Table of Neurotransmitters
Transmitter
Molecule

Derived
From

Acetylcholine

Choline

Serotonin
5-Hydroxytryptamine (5HT)

Tryptophan

GABA

Glutamate

Site of Synthesis
CNS, parasympathetic nerves
CNS, chromaffin cells of the gut,
enteric cells
CNS

Glutamate

CNS

Aspartate

CNS

Glycine

spinal cord

Histamine

Histidine

hypothalamus

Epinephrine
synthesis pathway

Tyrosine

adrenal medulla, some CNS cells

Norpinephrine
synthesis pathway

Tyrosine

CNS, sympathetic nerves

Dopamine
synthesis pathway

Tyrosine

CNS

Adenosine

ATP

CNS, peripheral nerves

sympathetic, sensory and enteric
nerves

ATP
Nitric oxide, NO

Arginine

CNS, gastrointestinal tract

Many other neurotransmitters are derived from precursor proteins, the socalled peptide neurotransmitters. As many as 50 different peptides have
been shown to exert their effects on neural cell function. Several of these
peptide transmitters are derived from the larger protein pre-opiomelanocortin
(POMC). Neuropeptides are responsible for mediating sensory and emotional
responses including hunger, thirst, sex drive, pleasure and pain. The
imbalance of ones neuropeptides can be a cause of chemical dependency.
Addiction rehabilitation centers are available for help and for more information,
check out the rehab guide or NIDA.
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Synaptic Transmission
Synaptic transmission refers to the propagation of nerve impulses from
one nerve cell to another. This occurs at a specialized cellular structure known
as the synapse, a junction at which the axon of the presynaptic neuron
terminates at some location upon the postsynaptic neuron. The end of a
presynaptic axon, where it is juxtaposed to the postsynaptic neuron, is
enlarged and forms a structure known as the terminal button. An axon can
make contact anywhere along the second neuron: on the dendrites (an
axodendritic synapse), the cell body (an axosomatic synapse) or the axons (an
axo-axonal synapse).
Nerve impulses are transmitted at synapses by the release of chemicals
called neurotransmitters. As a nerve impulse, or action potential, reaches the
end of a presynaptic axon, molecules of neurotransmitter are released into the
synaptic space. The neurotransmitters are a diverse group of chemical

compounds ranging from simple amines such as dopamine and amino acids
such as -aminobutyrate (GABA), to polypeptides such as the enkephalins.
The mechanisms by which they elicit responses in both presynaptic and
postsynaptic neurons are as diverse as the mechanisms employed by growth
factor and cytokine receptors.
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Neuromuscular Transmission
A different type of nerve transmission occurs when an axon terminates on
a skeletal muscle fiber, at a specialized structure called the neuromuscular
junction. An action potential occurring at this site is known as neuromuscular
transmission. At a neuromuscular junction, the axon subdivides into numerous
terminal buttons that reside within depressions formed in the motor end-plate.
The particular transmitter in use at the neuromuscular junction is acetylcholine.
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Neurotransmitter Receptors
Once the molecules of neurotransmitter are released from a cell as the
result of the firing of an action potential, they bind to specific receptors on the
surface of the postsynaptic cell. In all cases in which these receptors have
been cloned and characterized in detail, it has been shown that there are
numerous subtypes of receptor for any given neurotransmitter. As well as
being present on the surfaces of postsynaptic neurons, neurotransmitter
receptors are found on presynaptic neurons. In general, presynaptic neuron
receptors act to inhibit further release of neurotransmitter.
The vast majority of neurotransmitter receptors belong to a class of
proteins known as the serpentine receptors. This class exhibits a
characteristic transmembrane structure: that is, it spans the cell membrane,
not once but seven times. The link between neurotransmitters and intracellular
signaling is carried out by association either with G-proteins (small GTPbinding and hydrolyzing proteins) or with protein kinases, or by the receptor
itself in the form of a ligand-gated ion channel (for example, the acetylcholine
receptor). One additional characteristic of neurotransmitter receptors is that
they are subject to ligand-induced desensitization: That is, they can become
unresponsive upon prolonged exposure to their neurotransmitter.
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Acetylcholine

Acetylcholine (ACh) is a simple molecule synthesized from choline and

acetyl-CoA through the action of choline acetyltransferase. Neurons that
synthesize and release ACh are termed cholinergic neurons. When an action
potential reaches the terminal button of a presynaptic neuron a voltage-gated
calcium channel is opened. The influx of calcium ions, Ca 2+, stimulates the
exocytosis of presynaptic vesicles containing ACh, which is thereby released
into the synaptic cleft. Once released, ACh must be removed rapidly in order to
allow repolarization to take place; this step, hydrolysis, is carried out by the
enzyme, acetylcholinesterase. The acetylcholinesterase found at nerve
endings is anchored to the plasma membrane through a glycolipid.

Synthesis of Acetylcholine
ACh receptors are ligand-gated cation channels composed of four different
polypeptide subunits arranged in the form [(2)()()()]. Two main classes of
ACh receptors have been identified on the basis of their responsiveness to the
toadstool alkaloid, muscarine, and to nicotine, respectively: the muscarinic
receptors and the nicotinic receptors. Both receptor classes are abundant in
the human brain. Nicotinic receptors are further divided into those found at
neuromuscular junctions and those found at neuronal synapses. The activation
of ACh receptors by the binding of ACh leads to an influx of Na + into the cell
and an efflux of K +, resulting in a depolarization of the postsynaptic neuron and
the initiation of a new action potential.
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Cholinergic Agonists and Antagonists

Numerous compounds have been identified that act as either agonists or
antagonists of cholinergic neurons. The principal action of cholinergic agonists
is the excitation or inhibition of autonomic effector cells that are innervated by
postganglionic parasympathetic neurons and as such are referred to as
parasympathomimetic agents. The cholinergic agonists include choline
esters (such as ACh itself) as well as protein- or alkaloid-based compounds.
Several naturally occurring compounds have been shown to affect cholinergic
neurons, either positively or negatively.
The responses of cholinergic neurons can also be enhanced by
administration of cholinesterase (ChE) inhibitors. ChE inhibitors have been
used as components of nerve gases but also have significant medical

application in the treatment of disorders such as glaucoma and myasthenia

gravis as well as in terminating the effects of neuromuscular blocking agents
such as atropine.
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Natural Cholinergic Agonist and Antagonists

Source of Compound

Mode of Action

Agonists
alkaloid prevalent in the
tobacco plant

activates nicotinic class

of ACh receptors, locks
the channel open

alkaloid produced by
Amanita muscaria
mushrooms

activates muscarinic
class of ACh receptors

protein produced by the

black widow spider

induces massive ACh

release, possibly by
acting as a Ca2+
ionophore

atropine (and related

compound
Scopolamine)

alkaloid produced by the

deadly nightshade,
Atropa belladonna

blocks ACh actions only

at muscarinic receptors

Botulinus toxin

eight proteins produced

by Clostridium botulinum

inhibits the release of

ACh

-Bungarotoxin

protein produced by
Bungarus genus of
snakes

prevents ACh receptor

channel opening

active ingredient of curare

prevents ACh receptor

channel opening at motor
end-plate

Nicotine

Muscarine

-Latrotoxin

Antagonists

d-Tubocurarine

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Catecholamines
The principal catecholamines are norepinephrine, epinephrine and
dopamine. These compounds are formed from phenylalanine and tyrosine.
Tyrosine is produced in the liver from phenylalanine through the action of
phenylalanine hydroxylase. The tyrosine is then transported to catecholaminesecreting neurons where a series of reactions convert it to dopamine, to
norepinephrine and finally to epinephrine (see also Specialized Products of
Amino Acids).

Synthesis of the catecholamines from tyrosine

Catecholamines exhibit peripheral nervous system excitatory and

inhibitory effects as well as actions in the CNS such as respiratory stimulation
and an increase in psychomotor activity. The excitatory effects are exerted
upon smooth muscle cells of the vessels that supply blood to the skin and
mucous membranes. Cardiac function is also subject to excitatory effects,
which lead to an increase in heart rate and in the force of contraction. Inhibitory
effects, by contrast, are exerted upon smooth muscle cells in the wall of the
gut, the bronchial tree of the lungs, and the vessels that supply blood to
skeletal muscle.
In addition to their effects as neurotransmitters, norepinephrine and
epinephrine can influence the rate of metabolism. This influence works both by
modulating endocrine function such as insulin secretion and by increasing the
rate of glycogenolysis and fatty acid mobilization.
The catecholamines bind to two different classes of receptors termed the
- and -adrenergic receptors. The catecholamines therefore are also known
as adrenergic neurotransmitters; neurons that secrete them are adrenergic
neurons. Norepinephrine-secreting neurons are noradrenergic. Some of the
norepinephrine released from presynaptic noradrenergic neurons is recycled in
the presynaptic neuron by a reuptake mechanism.
The actions of norepinephrine and epinephrine are exerted via receptormediated signal transduction events. There are three distinct types of
adrenergic receptors: 1, 2, . Within each class of adrenergic receptor there
are several sub-classes. The 1 class contains the 1A, 1B, and 1D receptors.
The 1 receptor class are coupled to G q-type G-proteins that activate PLC
resulting in increases in IP3 and DAG release from membrane PIP 2. The 2
class contains the 2A, 2B, and 2C receptors. The 2 class of adrenergic
receptors are coupled to G i-type G-proteins that inhibit the activation of
adenylate cyclase and therefore, activation results in reductions in cAMP
levels. The class of receptors is composed of three subtypes: 1, 2, and 3
each of which couple to Gs-type G-proteins resulting in activation of adenylate
cyclase and increases in cAMP with concomitant activation of PKA.
Dopamine binds to dopamineric receptors identified as D-type receptors
and there are four subclasses identified as D 1, D2, D4, and D5. Activation of the
dopaminergic receptors results in activation of adenylate cyclase (D 1 and D5) or
inhibition of adenylate cyclase (D2 and D4).

Catecholamine Catabolism
Epinephrine and norepinephrine are catabolized to inactive compounds
through the sequential actions of catecholamine-O-methyltransferase (COMT)
and monoamine oxidase (MAO). Compounds that inhibit the action of MAO
have been shown to have beneficial effects in the treatment of clinical
depression, even when tricyclic antidepressants are ineffective. The utility of
MAO inhibitors was discovered serendipitously when patients treated for

tuberculosis with isoniazid showed signs of an improvement in mood; isoniazid

was subsequently found to work by inhibiting MAO.

Metabolism of the catecholamine neurotransmitters. Only clinically

important enzymes are included in this diagram. The catabolic byproducts of
the catecholamines, whose levels in the cerebrospinal fluid are indicative of
defects in catabolism, are in blue underlined text. Abbreviations: TH = tyrosine
hydroxylase, DHPR = dihydropteridine reductase, H 2B = dihydrobiopterin, H4B
= tetrahydrobiopterin, MAO = monoamine oxidase, COMT = catecholamine-Omethyltransferase, MHPG = 3-methoxy-4-hydroxyphenylglycol, DOPAC =
dihydroxyphenylacetic acid.
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Serotonin
Serotonin (5-hydroxytryptamine, 5HT) is formed by the hydroxylation and
decarboxylation of tryptophan (see also Specialized Products of Amino Acids).

Pathway for serotonin synthesis from tryptophan. Abbreviations: THP =

tryptophan hydroxylase, DHPR = dihydropteridine reductase, H 2B =
dihydrobiopterin, H4B = tetrahyrobiopterin, 5-HT = 5-hydroxytryptophan, AADC
= aromatic L-amino acid decarboxylase.

The greatest concentration of 5HT (90%) is found in the enterochromaffin

cells of the gastrointestinal tract. Most of the remainder of the body's 5HT is
found in platelets and the CNS. The effects of 5HT are felt most prominently in
the cardiovascular system, with additional effects in the respiratory system and
the intestines. Vasoconstriction is a classic response to the administration of
5HT.
Neurons that secrete 5HT are termed serotonergic. Following the release
of 5HT, a portion is taken back up by the presynaptic serotonergic neuron in a
manner similar to that of the reuptake of norepinephrine.
The function of serotonin is exerted upon its interaction with specific
receptors. Several serotonin receptors have been cloned and are identified as
5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7. Within the 5HT1 group there
are subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E (a putative 5HT receptor), and 5HT1F.
There are three 5HT2 subtypes, 5HT2A, 5HT2B, and 5HT2C. There are two 5HT5
subtypes, 5HT5a and 5HT5B in the human genome but the 5HT 5B gene is a
pseudogene. Most of these receptors are coupled to G-proteins that affect the
activities of either adenylate cyclase or phospholipase C. The 5HT 3 class of
receptors are ion channels.

Receptor
Family

Associated
G-Proteins

5HT1

Gi/Go
see the Signal Transduction
page for description of
various G-proteins

inhibits cAMP production,

inhibitory neurotransmission

5HT2

Gq/G11

increased production of DAG

and IP3, excitatory
neurotransmission

5HT3

ligand-gated Na+ and K+

channels

Result of Receptor
Activation

depolarizes axonal membrane,

excitatory neurotransmission

5HT4

Gs

increases cAMP production,

excitatory neurotransmission

5HT5

Gi/Go

inhibits cAMP production,

inhibitory neurotransmission

5HT6

Gs

increases cAMP production,

excitatory neurotransmission

5HT7

Gs

increases cAMP production,

excitatory neurotransmission

Some serotonin receptors are presynaptic and others postsynaptic. The

5HT2A receptors mediate platelet aggregation and smooth muscle contraction.
The 5HT2C receptors are suspected in control of food intake as mice lacking
this gene become obese from increased food intake and are also subject to
fatal seizures. The 5HT 3 receptors are present in the gastrointestinal tract and
are related to vomiting. Also present in the gastrointestinal tract are 5HT 4
receptors where they function in secretion and peristalsis. The 5HT 6 and 5HT7
receptors are distributed throughout the limbic system of the brain and the
5HT6 receptors have high affinity for antidepressant drugs.

Receptor
Sub-Type

Sites of
Expression

Functions

vasculature, CNS

aggression, anxiety, blood pressure

(vasoconstriction), appetite, memory,
mood, cardiovascular tone, heart rate,
respiration, pupillary dilation, nociception
(pain sensation), sexual behavior, erectile
function, emesis (vomiting),
thermoregulation, sleep, addictive
behaviors

5HT1B

vasculature, CNS

locomotion, aggression, anxiety, blood

pressure (vasoconstriction), memory,
mood, learning, sexual behavior, erectile
function, addictive behaviors

5HT1D

vasculature, CNS

blood pressure (vasoconstriction),

locomotion, anxiety

5HT1F

CNS

5HT1A

5HT2A

gastrointestinal
tract, smooth
muscles,
vasculature, CNS,
PNS, platelets

involved in migraine headaches

anxiety, blood pressure
(vasoconstriction), thermoregulation,
appetite, learning, memory, mood,
cognitive abilities, sexual behavior, sleep,
addictive behaviors

5HT2B

gastrointestinal
tract, smooth
muscles,
vasculature, CNS,
PNS, platelets

gastrointestinal, motility, blood pressure

(vasoconstriction), appetite, anxiety, sleep

5HT2C

gastrointestinal
tract, smooth
muscles,
vasculature, CNS,
PNS, platelets

anxiety, locomotion, gastrointestinal

motility, blood pressure
(vasoconstriction), appetite, mood, sexual
behavior, erectile function,
thermoregulation, sleep, addictive
behaviors

5HT3

gastrointestinal
tract, CNS, PNS

anxiety, gastrointestinal motility, emesis

(vomiting), learning, memory, addictive
behaviors

5HT4

gastrointestinal
tract, CNS, PNS

respiration, appetite, gastrointestinal

motility, learning, memory, mood, anxiety

5HT5A

CNS

locomotion, sleep

5HT6

CNS

cognitive abilities, learning, memory,

anxiety, mood

5HT7

gastrointestinal
tract, vasculature,
CNS

blood pressure (vasoconstriction),

respiration, thermoregulation, sleep,
memory, mood, anxiety

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GABA
Several amino acids have distinct excitatory or inhibitory effects upon the
nervous system. The amino acid derivative, -aminobutyrate, also called 4aminobutyrate, (GABA) is a well-known inhibitor of presynaptic transmission in
the CNS, and also in the retina. Neurons that secrete GABA are termed
GABAergic.
The formation of GABA occurs by the decarboxylation of glutamate
catalyzed by glutamate decarboxylase (GAD). GAD is present in many nerve
endings of the brain as well as in the -cells of the pancreas. The activity of

GAD requires pyridoxal phosphate (PLP) as a cofactor. PLP is generated from

the B6 vitamins (pyridoxine, pyridoxal, and pyridoxamine) through the action of
pyridoxal kinase. Pyridoxal kinase itself requires zinc for activation. A
deficiency in zinc or defects in pyridoxal kinase can lead to seizure disorders,
particularly in seizure-prone preeclamptic patients (hypertensive condition in
late pregnancy).

GABA synthesis
GABA exerts its effects by binding to two distinct receptors, GABA-A and
GABA-B. The GABA-A receptors form a Cl channel. The binding of GABA to
GABA-A receptors increases the Cl- conductance of presynaptic neurons. The
anxiolytic drugs of the benzodiazepine family exert their soothing effects by
potentiating the responses of GABA-A receptors to GABA binding. The GABAB receptors are coupled to an intracellular G-protein and act by increasing
conductance of an associated K+ channel.
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Michael W King, PhD | 19962011 themedicalbiochemistrypage.org, LLC | info
@ themedicalbiochemistrypage.org
Last modified: October 27, 2011